Stable oral solutions for combined api

ABSTRACT

The present invention relates to a homogeneous, stable, and palatable pharmaceutical solution comprising baclofen, sorbitol and naltrexone.

The present invention relates to novel pharmaceutical compositionscomprising baclofen, sorbitol and naltrexone and the uses thereof.

The novel pharmaceutical compositions of the invention are useful in thetreatment of nervous system diseases such as e.g. Charcot-Marie-Toothdisease, neuropathic pain, drug or alcohol withdrawal, or Parkinson'sdisease.

It has been recently shown (WO2010/139627) that an oral combinatorialtreatment based on the oral administration, as active ingredients, ofbaclofen, sorbitol and naltrexone is efficient in treatingCharcot-Marie-Tooth disease (CMT). As these active pharmaceuticalingredients (APIs) may be used in highly heterogeneous amounts, there isa need for a galenic form that offers a homogeneous distribution of APIsin the medicament while respecting physico-chemical requirements of eachdrug to ensure their stability and, being easily swallowed, encouraginggood compliance.

Baclofen is a muscle relaxant which has been approved for treatingtransient spasticity and which is currently under development for thetreatment of alcohol dependence and alcohol withdrawal. It is aderivative of gamma-aminobutyric acid (GABA) and acts as an agonist forthe GABAB receptors [1]. It has been commercialized under variouspharmaceutical forms as muscle relaxant. It is currently marketed undertablet form and solution (by instance, Lioresal, 5 mg/5 mL) for oraladministration. Liquid formulations for infusion have also beendeveloped, as well as creams for topical application in conjunction withother muscle relaxant, anti-inflammatory and/or analgesic drugs.Baclofen is known as poorly soluble in aqueous solutions and strongacids or bases required for increasing baclofen solubility are oftenharmful and incompatible with drug safety requirements [2]. Intrathecaltreatment (such as Lioresal intrathecal, developed by Novartis) is atreatment of choice in patients who are unresponsive to or cannottolerate oral therapy [3]. Moreover this route is believed to be moreefficient than oral route in treating severe spastic events. In thisregard, several artificial cerebrospinal fluids have been also developedfor intrathecal administration of baclofen. WO2008/157288 disclosesliquid formulations for baclofen concentration ranking from 2 mg/mL to10 mg/mL, consisting in a complex multivalent physiological ionsolution.

Sorbitol, or glucitol, is a natural sugar-alcohol naturally found insome fruits and berries. It is mainly used as a food additive (E420),highly soluble in water whereas poorly soluble in ethanol, commonly usedas sweetener, notably as sugar-substitute in diet foods, although thesweetness of sorbitol is poor (about half that of sucrose) compared toother sugar-substitute such as stevioside (about 200 times higher thansucrose) [4]. Sorbitol may also serve as humectant, viscositycontrolling, bulking and preservative agent. In this context it can beprovided in its crystalline form, powder or in solution, as a 70% weightsolution. Because of these features and of its high stability, it isbroadly used in processed foods, cosmetics and pharmaceuticals. InEurope, sorbitol is also commercialized as an osmotic laxative medicine.Liquid rectal formulation is marketed at a concentration of 4.465 g/5mL. Sorbitol is also used in irrigation solution (for example, SorbitolIrrigant, 3.3 g/100 mL).

Naltrexone is a broad-spectrum opioid antagonist that is mainly used inthe treatment of alcohol and opiate dependences. It is a small moleculeable to cross the blood brain bather. Its hydrochloride salt is thepreferred form and pharmaceutical forms encompass oral forms (e.g.capsules, solution, and polymeric microspheres), injectable formulationas well as implants. Naltrexone mainly reduces heavy drinking andcraving behaviors [5] and acts by blocking the effects of heroin.Studies have shown that the compliance is more related to the patientpopulation than the administration route (implanted sustained releasedevices versus oral tablets) [6-8]. Oral solutions for naltrexone areprovided at concentrations ranking from 1 to 5 mg per mL.

There is a wide variety of dosage forms for administering drugs orcombinations of drugs. The choice of the galenic form for a medicine isgoverned by several criteria which are for example: the inherentphysico-chemical properties of the API and the potential compatibilityissues between mixed APIs and/or the excipients, metabolism of the API,compatibility between patient's condition and the route ofadministration (for instance the patient's capacity to swallow),potential impact of the dosage form on the compliance of patients(palatability, convenience of use), development and production costs(the medicine should be as affordable as possible for patient) andstorage requirements.

Most common oral dosage forms are tablets, capsules, and liquidformulations.

Because of the ease and convenience of their use, tablets account formost of the dosage form of the majority of medicines. They are soliddosage forms containing the API(s) and most often excipient(s) and/orcarrier(s) which can be molded or compressed to obtain tablets ofvarious sizes and shapes.

Capsules are another oral dosage form consisting in a shell within whichAPI(s) are enclosed, in a powder or granular form. Nevertheless, thelatter may have the inconvenient to be hard to swallow, especially forchildren, elderly persons or patients with a swallowing-affectingdisease especially when API quantities necessitate large conditioning.

Suspensions are liquid formulations comprising not soluble solidparticles dispersed in a solvent. Suspensions can be sold in liquid formwhich needs to be well shaken before use to avoid variability in dosage.Alternatively, they can be dispensed in a solid form (unit doses ofpowder) to be diluted upon use. Suspensions are also used in thepreparation of tablets implying the use of a carrier excipient which issolid below a given temperature and liquid above another. This allowsobtaining tablets within which active pharmaceutical ingredients arehomogeneously dispersed.

Solutions are also liquid formulations within which molecules of APIsand other compounds such as excipients are typically homogeneouslydispersed in a solvent. The difference with suspensions is the completedissolution of API(s) in the vehicle. Pharmaceutical syrups are viscousliquids comprising a minimal dose of sucrose as defined in thepharmacopeia and at least one API. When medical concerns impede the useof sugar, sucrose is replaced by sugar substitutes or artificialsweetener admixed with a thickener. A concern with solutions is thatAPIs are more susceptible to chemical instability than in the otherdosage forms. Moreover solutions need to be carefully handled to avoidpotential microbial contaminations that may provoke degradation of APIsand/or cause patient intoxication.

To date, there is no formulation combining baclofen, sorbitol andnaltrexone in a sole, stable and compliance-compatible pharmaceuticalproduct. As stated above, baclofen and naltrexone are commercializedunder liquid as well as solid formulations (e.g. Lioresal, Antaxone).Sorbitol is commercialized as a powder (Sorbitol Delalande, 5 g, SanofiAventis) to be used as an oral suspension or in a liquid form for rectalinjection (Microlax).

Thus, there is an important need for a stable, homogeneous despite ofgreat differences between the APIs concentrations, and compliancepromoting formulation of such medicines suitable for the long termtreatment of CMT, which is an orphan invalidating chronic disease.

SUMMARY OF THE INVENTION

The invention relates to novel oral compositions suitable foradministration of combined APIs such as baclofen, sorbitol andnaltrexone. The compositions are stable over time and particularlyadapted for repeated intake in human subjects.

More particularly, an object of the invention resides in apharmaceutical composition comprising, in the form of a solution:

-   -   baclofen, sorbitol, and naltrexone,    -   an acetate or citrate buffer having a pH comprised between 4 and        7, preferably between 4.5 and 5.5, and    -   optionally, at least one preservative and/or at least one        flavoring agent.

A further object of the invention relates to a method for preparing acomposition as defined above, comprising providing baclofen, sorbitoland naltrexone and admixing said active ingredients in solution in acitrate or acetate buffer having a pH comprised between 4 and 7.

The compositions of the invention may comprise further ingredients orexcipients. They may be formulated in any suitable device such as atube, flask, plastic or glass unit doses, stick packs, ampoule, pipette,etc.

Another object of the invention resides in a method for treating CMT ina human subject, comprising administering to the subject a compositionof the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel pharmaceutical compositions inthe form of liquid solutions comprising baclofen, sorbitol andnaltrexone as active pharmaceutical ingredients (“APIs”). Morespecifically, the liquid solutions of the invention comprise the APIs, abuffer solution having a pH comprised between 4 and 7, preferably acitrate or acetate buffer solution, and, optionally, at least onepreservative and/or at least one flavoring agent. As documented, suchliquid formulations allow stable and homogeneous combination of said atleast three drugs, even when used at very different relativeconcentrations, for instance of about 8.6/300/1 (weight ratio,respectively), and favors compliance.

DEFINITIONS

Within the context of this invention, the term “solution” refers to amixture of one or more substances dispersed molecularly (i.e.,dissolved) in a dissolving liquid medium or vehicle. The solution ispreferably homogeneous, in the sense that each API is essentiallyuniformly distributed and concentrated in the solution. The liquidsolution may be viscous (such as syrup) or not. As already mentioned, aliquid solution differs from a suspension which comprises solidparticles dispersed throughout a liquid phase in which they are notsoluble.

The terms “stable” and “stability” mean that the evolution of theproduct with time and/or under specific environmental conditions (i.e.,temperature, humidity, etc.) has no significant effects on its quality,safety and/or efficacy for a given time period. It can be measuredthrough the formation of degradation products (impurities), variation ofpH, appearance, microbial growth, and/or color as exemplified in theexperimental section. Typically, compositions according to the inventionare considered as stable if at least 95% of the initial concentration ofeach of the APIs is found after 4 weeks at 25° C., and/or if nosubstantial change in the appearance of the solution is observed duringsuch a period of time and under such temperature conditions. Stabilityis more preferably assessed under 60% relative humidity conditions.

Compositions

The invention relates to pharmaceutical compositions in the form ofliquid solutions, suitable for oral intake, which comprise:

-   -   baclofen, sorbitol and naltrexone,    -   a buffer solution having a pH comprised between 4 and 7,        preferably a citrate or acetate buffer solution, and    -   optionally, at least one preservative and/or at least one        flavoring agent.

As exemplified in the experimental section, such liquid formulationsfavor the homogeneous dispersion of the APIs, are not prone to microbialcontamination, and show a good stability for each of the APIs.Accordingly, the formulation of the three active ingredients in a uniquedosage form is of great interest in the case of this medicine which mayneed to be taken all life long and for which a good compliance istherefore necessary. In a particular embodiment, the unit dosage formcomprises 1, ½, ⅓ or ¼ of the daily therapeutic dose of the composition.In a preferred embodiment, the unit dosage form comprises half the dailytherapeutic dose of the composition.

The Active Pharmaceutical Ingredients

The invention relates to novel compositions comprising, as APIs, acombination of at least baclofen, sorbitol, and naltrexone. IllustrativeCAS number(s) are provided in table 1 below.

TABLE 1 Active pharmaceutical ingredients CAS number Baclofen63701-56-4, 1134-47-0 Sorbitol 50-70-4 Naltrexone 16676-29-2, 16590-41-3

In the compositions of the invention, the APIs may be either in form ofthe chemical compounds as specifically named or in the form of anyacceptable salts, hydrates, derivatives, isomers, racemates, conjugatesand/or pro-drugs thereof.

The term “salt” refers to a pharmaceutically acceptable and relativelynon-toxic, inorganic or organic acid or base addition salt of the APIsof the composition of the present invention. Pharmaceutical saltformation consists in pairing an acidic, basic or zwitterionic drugmolecule with a counterion to create a salt version of the drug. A widevariety of chemical species can be used in neutralization reaction.Pharmaceutically acceptable salts thus include those obtained byreacting the main compound, functioning as a base, with an inorganic ororganic acid to form a salt, for example, salts of acetic acid, nitricacid, tartric acid, hydrochloric acid, sulfuric acid, phosphoric acid,methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,succinic acid or citric acid. Pharmaceutically acceptable salts includethose in which the compound functions as an acid and is reacted with anappropriate base to form, e.g., sodium, potassium, calcium, magnesium,ammonium, or choline salts. Salt selection is now a common standardoperation in the process of drug development as taught by H. Stahl andC. G Wermuth in their handbook [9].

The term “prodrug” as used herein refers to any functional derivatives(or precursors) of an API of the present invention, which, whenadministered to a biological system, generates said API as a result ofe.g., spontaneous chemical reaction(s), enzyme catalysed chemicalreaction(s), and/or metabolic chemical reaction(s). Prodrugs are usuallyinactive or less active than the resulting drug and can be used, forexample, to improve the physicochemical properties of the drug, totarget the drug to a specific tissue, to improve the pharmacokinetic andpharmacodynamic properties of the drug and/or to reduce undesirable sideeffects. Some of the common functional groups that are amenable toprodrug design include, but are not limited to, carboxylic, hydroxyl,amine, phosphate/phosphonate and carbonyl groups. Prodrugs typicallyproduced via the modification of these groups include, but are notlimited to, esters, carbonates, carbamates, amides and phosphates.Specific technical guidance for the selection of suitable prodrugs isgeneral common knowledge [10-13]. Furthermore, the preparation ofprodrugs may be performed by conventional methods known by those skilledin the art. Methods which can be used to synthesize other prodrugs aredescribed in numerous reviews on the subject [11, 14-18]. For example,arbaclofen placarbil, listed in ChemID plus Advance database (website:chem.sis.nlm.nih.gov/chemidplus/), is a well-known prodrug ofbaclofen[19, 20] which could be used instead of baclofen in compositionsof the invention. Specific examples of other prodrugs of baclofen aregiven in Hanafi et al, 2011 [21], particularly baclofen esters andbaclofen ester carbamates. Other prodrugs of baclofen can be found inthe following patent applications: WO2010/102071, US2009197958,WO2009/096985, WO2009/061934, WO2008/086492, US2009216037,WO2005/066122, US2011021571, WO2003/077902 and WO2010/120370.

The term “derivative” of a compound includes any molecule that isfunctionally and/or structurally related to said compound, such as anacid, amide, ester, ether, acetylated variant, hydroxylated variant, oran alkylated (C1-C6) variant of such a compound. The term derivativealso includes structurally related compound having lost one or moresubstituent as listed above. Preferred derivatives of a compound aremolecules having a substantial degree of similarity to said compound, asdetermined by known methods. Similar compounds along with their index ofsimilarity to a parent molecule can be found in numerous databases suchas PubChem (http://pubchem.ncbi.nlm.nih.gov/search/) or DrugBank(http://www.drugbank.ca/). In a more preferred embodiment, derivativesshould have a Tanimoto similarity index greater than 0.4, preferablygreater than 0.5, more preferably greater than 0.6, even more preferablygreater than 0.7 with a parent drug. The Tanimoto similarity index iswidely used to measure the degree of structural similarity between twomolecules. Tanimoto similarity index can be computed by software such asthe Small Molecule Subgraph Detector [22, 23] available online(http://www.ebi.ac.uk/thornton-srv/software/SMSD/). The term“derivative” also encompasses any metabolite of said APIs, i.e. modifiedor processed drug that retains at least part of the activity of theparent drug.

Particularly preferred APIs are (RS) baclofen, D-sorbitol and naltrexoneHCl.

Buffer

As indicated, the pharmaceutical compositions of the invention combineAPIs in a suitable buffer. The inventors have indeed found particularbuffer conditions which make it possible to combine in a single, oralsolution, three distinct APIs in highly different concentrations, whilepreserving stability and safety thereof. More particularly, theinvention shows that a suitable buffer shall have a pH comprised between4 and 7, more preferably between 4 and 6, even more preferably between4.5 and 5.5. Furthermore, the inventors have surprisingly found that agood stability and a homogeneous solution can be obtained when theingredients are formulated in an acetate or citrate buffer. Mostremarkably, such formulations are less prone to microbial contamination(such as bacterial contamination), even in the absence of apreservative.

In this regard, a preferred object of the invention relates to apharmaceutical composition in the form of a liquid solution, suitablefor oral intake, which comprises:

-   -   baclofen, sorbitol and naltrexone,    -   a citrate or acetate buffer solution having a pH comprised        between 4 and 7, and    -   optionally, a preservative and/or a flavoring agent.

As exemplified in the experimental section, the liquid solutions of theinvention allow maintaining the stability of the APIs in accordance withthe guidance of the main national health authorities. The liquidformulations of the invention allow a homogeneous dispersion of theAPIs, are not prone to microbial contamination, and show a goodstability for each of the APIs.

In a preferred embodiment, the selected acetate or citrate buffer has apH of or comprised between 4.5 and 5.5.

In a more preferred embodiment, the selected acetate or citrate bufferhas a pH of about 5.5.

Surprisingly, the experimental results show that acetate or citratebuffers, as compared to other buffers (e.g., phosphate) confer highstability, no or low contamination, and highly homogeneous liquidformulations of the three APIs. The compositions of the invention,particularly with acetate buffer, are highly stable and resistant tomicrobial contamination, even in the absence of a preservative. Moreparticularly, inventors have also observed that there is no need for anypreservative for solutions comprising acetate buffer as a vehicle tosatisfy stability conditions.

In this regard, a particular object of the invention relates to apharmaceutical composition in the form of a liquid solution, suitablefor oral intake, which comprises:

-   -   baclofen, sorbitol and naltrexone,    -   an acetate buffer solution having a pH comprised between 4 and        7, preferably between 4.5 and 5.5, and    -   optionally, a flavoring agent.

Typically, such a composition is devoid of a preservative. Morepreferably, such a composition is devoid of a parahydroxybenzoate(paraben) compound.

Consequently, in a particular embodiment, such composition isparticularly suitable for use in children.

In another particular embodiment, such a paraben free composition ispackaged in unit doses. Such unit dosage form comprises 1, ½, ⅓ or ¼ ofthe daily therapeutic dose of the composition. In a preferredembodiment, the unit dosage form comprises half the daily therapeuticdose.

The components of the compositions may be used at differentconcentrations or relative ratios, which may be adjusted by the skilledperson.

In an embodiment, baclofen and naltrexone are present in a relativeweight ratio baclofen/naltrexone comprised between 2 and 20, preferablybetween 5 and 10 and more preferably of about 8.6.

In a preferred embodiment, sorbitol and naltrexone are present in arelative weight ratio sorbitol/naltrexone comprised between 100 and 500,preferably comprised between 200 and 400, more preferably of about 300.

In a preferred embodiment, baclofen, sorbitol and naltrexone are presentin the solution in a relative weight ratio baclofen/sorbitol/naltrexoneof x/y/1, with x being comprised between 2 and 20, preferably between 5and 10 and more preferably of about 8.6, and y being comprised between100 and 500, preferably comprised between 200 and 400, more preferablyof about 300.

In this regard, an object of the invention is a pharmaceuticalcomposition in the form of a solution comprising baclofen, sorbitol andnaltrexone in a relative weight ratio baclofen/sorbitol/naltrexone ofx/y/1, with x being comprised between 2 and 20, preferably between 5 and10 and more preferably of about 8.6, and y being comprised between 100and 500, preferably comprised between 200 and 400, more preferably ofabout 300.

In another embodiment, naltrexone is present in the solution at a finalconcentration comprised between 1 and 200 μg/mL, preferably between 10and 100 μg/mL.

In a particular embodiment, naltrexone concentration is about 7 μg/mL.

In another particular embodiment, naltrexone concentration is about 14μg/mL.

Compositions based on such low doses (i.e. naltrexone concentrationequal to about 7 or 14 μg/mL) are of particular interest for thepediatric use. Thus, in a particular embodiment, such compositions areparticularly suitable for pediatric formulation.

In a preferred embodiment, naltrexone concentration is about 70 μg/mL.

In another preferred embodiment, naltrexone concentration is about 140μg/mL.

In a particular embodiment, concentration of the vehicle, e.g. citrateor acetate buffer, of the solutions according the invention is 0.2 M.

In a more particular embodiment, a solution according to the inventionis free of any paraben compound and comprises:

-   -   baclofen, sorbitol and naltrexone as active ingredients in a        relative weight ratio of about 8.6/300/1 respectively, and    -   an acetate buffer as a vehicle at a pH of about 5.5, and    -   optionally, a flavoring agent.

Such compositions are particularly advantageous since, despite the lackof scientific evidence about any potential toxicity of parabens,paraben-free compositions are preferred.

Preservatives

Depending on the dosage and/or pH and/or nature of the buffer, it may bedesirable to add to the composition a preservative, to further increasethe stability thereof.

Preservatives may be selected from pharmaceutically-acceptablepreservatives such as parabens, ascorbic acid, ascorbyl palmitate,benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene,calcium ascorbate, calcium propionate, calcium sorbate, caprylic acid,dilauryl thiodipropionate, erythorbic acid, gum guaiac, glutathione,potassium bisulfite, potassium metabisulfite, potassium sorbate,propionic acid, propyl gallate, sodium ascorbate, sodium benzoate,sodium bisulfite, sodium metabisulfite, sodium propionate, sodiumsorbate, sodium sulfite, sorbic acid, stannous chloride, sulfur dioxide,thiodipropionic acid, and/or tocopherols.

Accordingly, in an embodiment, the invention relates to a solutioncomprising:

-   -   baclofen, sorbitol and naltrexone as active ingredients,    -   a citrate or acetate buffer with a pH of or comprised between 4        and 7, preferably a pH of or comprised between 4.5 to 5.5, and    -   at least one preservative.

More particularly, the addition of at least one paraben compound hasbeen proved efficient in impeding microbial growth which is particularlyadvantageous for a liquid oral formulation. The at least one parabencompound can be chosen from benzylparaben, butylparaben, ethylparaben,isobutylparaben, isopropylparaben, methylparaben, propylparaben, or anyof their salt. Sodium methylparaben and sodium propylparaben areparticularly preferred.

Accordingly, in an embodiment, the invention relates to a solutioncomprising:

-   -   baclofen, sorbitol and naltrexone as active ingredients,    -   a citrate buffer with a pH of or comprised between 4 and 7,        preferably a pH of or comprised between 4.5 to 5.5, and    -   at least one paraben.

In another embodiment, the invention relates to a solution comprising:

-   -   baclofen, sorbitol and naltrexone as active ingredients,    -   an acetate buffer with a pH of or comprised between 4 and 7,        preferably a pH of or comprised between 4.5 to 5.5, and    -   at least one paraben.

In a particular embodiment, the at least one paraben compound is amethyl paraben and/or a propyl paraben. In a more particular embodiment,the at least one paraben compound is sodium methyl paraben and/or sodiumpropyl paraben. The sodium methyl paraben and/or sodium propyl parabenmay be used in a concentration of about 0.18% w/v and about 0.02% w/v,respectively. As exemplified in experimental section, the inventors havefound stable solutions in which APIs are not prone to degradation atparaben concentrations far below the safe doses according to theEuropean Medicines Agency guidelines, i.e. 166 mg/day for methyl parabenand 50 mg/day for propyl paraben[24]. This is of particular interest foruse in children or in lifelong/chronic treatments.

Then, in an embodiment, the doses of methyl paraben and propyl parabenare less than 166 and 50 mg/day, respectively.

In a preferred embodiment, the doses of methyl and propyl parabens areless than 80 and 25 mg/day, respectively.

In a more preferred embodiment, doses of methyl and propyl parabens areabout 18 and 2 mg/day.

In an even more preferred embodiment, compositions of the invention arefree of parabens.

Flavoring Agent

In a particular embodiment, the compositions of the invention furthercontain at least one flavor or flavoring agent. Such agents can mask thetaste of the APIs and/or other compounds such as buffer, and facilitateoral intake. Flavoring agents can be either extracted from naturalsources, such as essential oils from flowers, fruits or roots, orartificially synthesized. A large variety of pharmaceutically-acceptableflavoring agents can be used. Preferred flavoring agents are notinterfering with the quantification of APIs, and not disrupting thestability of the formulations of the invention. The flavor should beadjusted as a function of its ability to mask the unpalatable taste.Flavoring agents may be selected from pharmaceutically acceptableflavors such as vanillin, isoamyl acetate, acetaldehyde, acetoin,aconitic acid, anethole, benzaldehyde, N-butyric acid, D- or L-carvonecinnamaldehyde, citral, decanal, diacetyl, ethyl acetate, ethylbutyrate, ethyl vanillin, eugenol, geraniol, geranyl acetate, glyceroltributyrate limonene, linalool, linalyl acetate, 1-malic acid, methylanthranilate, 3-methyl-3-phenyl glycidic acid, ethyl ester, orpiperonal. Preferred flavoring agents are vanillin or isoamyl acetate(banana oil).

A preferred solution according to the invention thus comprises:

-   -   baclofen, sorbitol and naltrexone as active ingredients,    -   an acetate or citrate buffer as a vehicle with a pH of or        comprised between 4 and 7, and more preferably of or comprised        between 4.5 and 5.5,    -   optionally at least one preservative, and    -   a flavoring agent, preferably selected from vanillin or isoamyl        acetate.

When using acetate buffer as a vehicle, isoamyl acetate is particularlypreferred. Preferred concentration for isoamyl acetate is between 0.1 to2.0 mg/mL, and more preferably of about 0.4 mg/mL.

Consequently, a more preferred solution according to the inventioncomprises:

-   -   baclofen, sorbitol and naltrexone as active ingredients,        preferably in a relative weight ratio of about 8.6/300/1        respectively,    -   acetate buffer as a vehicle with a pH comprised between 4 and 7,        preferably between 4.5 and 5.5, and    -   isoamyl acetate, preferably at a concentration comprised between        0.1 and 2.0 mg/mL.

Specific examples of compositions of the invention are detailed in table2 below.

TABLE 2 Ingredients per 1 mL of composition no No 1 No 2 No 3 No 4 No 5No 6 D-sorbitol (mg) 4.2 4.2 21 21 42 42 Naltrexone HCl (mg) 0.014 0.0140.07 0.07 0.14 0.14 RS baclofen (mg) 0.12 0.12 0.6 0.6 1.2 1.2 Acetatebuffer pH 5.5 to 1 mL Sodium methyl 1.8 — 1.8 — 1.8 — paraben (mg)Sodium propyl 0.2 — 0.2 — 0.2 — paraben (mg) Isoamyl acetate 0.4 0.4 0.40.4 0.4 0.4 (banana oil) (mg)

Further Compounds

Additional compounds which are compatible with oral pharmaceuticalformulations can be added to the formulation of the invention as needsidentified by the one skilled in the art. It can be, for example, atleast one other compatible drug or dietary supplement, other compatibleexcipient, as sugar or sweetener, coloring agent, antioxidant, viscositymodifier, flavor enhancer, co-solvent or preservative.

For example sweeteners or sugars can be chosen from: dextrose,glycerine, maltitol, stevia, aspartame, sucralose, neotame, acesulfamepotassium, and/or saccharin. Depending of the amount of sugar added tothe solution, a syrup can be obtained that might be considered as anadvantageous formulation in the case where the solution is specificallyformulated for children.

Examples of coloring agents are E 102 (Tartazine), E 103 (Chrysoine S),E 104 (Quinoline Yellow), E 105 (Fast Yellow AB), E 110 (Orange YellowS, Sunset Yellow FCF), E 111 (Orange GGN), E 120 (Cochineal, carminicacid), E 122 (Azorubin, Carmoisine), E 123 (Amaranth), E 124 (CochinealRed A, Ponceau 4 R), E 125 (Scarlet GN), E 126 (Ponceau 6 R), E 131(Patent Blue V), E 132 (Indigotin indigo carmine), E 141 (Coppercomplexes of chlorophylls and chlorophyllins), E 151 (Brilliant BlackBN, Black PN), E 152 (Black 7984), E 153 (Carbo medicinalis vegetalis(charcoal)), E 160 (a), (Alpha-, Beta-, Gamma-Carotene), E 160 (b)(Bixin and Norbixin (Roucou, Annatto)), E 162 (Beetroot red, betanin), E171 (Titanium dioxide), E 172 (Iron oxides and hydroxides), or E 181(Burnt umber).

In an embodiment, the invention relates to method for preparing one ofthe above compositions, comprising providing baclofen, sorbitol andnaltrexone and admixing said active ingredients in solution in a citrateor acetate buffer having a pH comprised between 4 and 7. The method mayfurther comprise adding to the solution one or more further agents suchas, in particular, a preservative and/or a flavoring agent. Thecompositions may also further comprise additional active agents.

A particular method for preparing a composition of the inventioncomprises the steps of:

-   -   i) preparing a solution by:        -   dispensing about 20% of the desired final volume of acetate            buffer (e.g., 0.17 M),        -   then dissolving sodium methyl paraben and sodium propyl            paraben,        -   then heating to 45-55° C., preferably about 50° C., with            stiffing until dissolving,        -   then cooling to about 25-35, typically about 30° C.;    -   ii) preparing another solution by:        -   dispensing about 70% of the desired final volume of acetate            buffer (e.g., 0.17 M),        -   then adding sorbitol, naltrexone and baclofen,        -   then mixing until dissolving;    -   iii) mixing the solutions obtained in step i) and ii),        preferably under gentle agitation for 5 minutes,    -   iv) adding a flavoring agent (e.g., banana flavor) to the        solution obtained in step    -   iii) and mixing until dissolving,    -   v) if needed, adjusting pH to 5.4-5.6 with 50% w/w NaOH solution        or glacial acetic acid (>99.0%), and    -   vi) making up to the final volume with acetate buffer (e.g.,        0.17 M).

Another suitable method for preparing a composition of the inventioncomprises the steps of:

-   -   i) dispensing about 90% water of the total batch sized required,    -   ii) optionally adding sodium methyl paraben and sodium propyl        paraben, then mixing until dissolving,    -   iii) adding sodium acetate trihydrate and glacial acetic acid,        then mixing until dissolving,    -   iv) adding sorbitol, naltrexone and baclofen,    -   v) adding isoamyl acetate, then mixing until dissolving,    -   vi) if needed, adjusting pH to 5.4-5.6 with a 50% w/w NaOH        solution or glacial acetic acid (>99.0%), and    -   vii) making up weight with water.

The composition may be packaged in any suitable device or container,such as a flask, bottle, glass or plastic unit-dose container such asstick-pack, tube, ampoule, etc., typically under sterile conditions.More commonly the pharmaceutical formulations of the invention areprescribed to the patient in “patient packs” containing a number dosingunits or other means for administration of metered unit doses for useduring a distinct treatment period in a single package, usually ablister pack. The inclusion of a package insert has been shown toimprove patient compliance with the physician's instructions. Thepatient packs encompass sets of single-dose sachets or ampoulescontaining the suitable amount of the liquid formulation as disclosedherein.

Alternatively, they can be supplied in a larger container as a bottle,then the invention also relates to pharmaceutical kit of partscomprising a bottle containing any liquid formulation as disclosedherein, a cap and/or a pipette or a pipette-cap system, and optionallyinstructions.

The bottle can be made of any material convenient with the storage andthe use requirements comprising polymers, metal and glass and so on. Itis of importance that the bottle material does not interfere with thecomponents of the liquid formulation as disclosed herein. In anembodiment it is made of glass. In order to protect the APIs fromlight-induced degradation, a preferred embodiment comprises amber glassbottle.

The bottle capacity can be adapted to the volume to be administrated forthe period during which the liquid formulation as disclosed herein isstable. For instance, a solution which is stable for 10 days afteropening associated to an administration of two doses of 5 mL per day maybe stored into bottle of about 100 mL. The one skilled in the art willeasily adapt the volume of the bottle to that needed as previouslysuggested.

The pipette is made of glass, plastic or any material convenient withthe use and the storage of the liquid solutions as disclosed herein. Thepipette may be graduated to facilitate the administration of the liquidsolution. In an embodiment, the pipette is a 5 mL graduated pipette.

The cap (or closure) is any article for closing a suitably shapedopening. It encompasses, but is not limited to, childproof closures,waterproof closures, pipette-associated caps, solid caps, plastic orpolymeric caps. In an embodiment, the cap is screwed on the bottle topor interlocked with the top of the bottle.

A sealing element may be required for the tightness of the systembottle-cap or bottle-pipette-cap or bottle-pipette or pipette-cap. Thiselement can be supplied on its own and further fit in the bottle-neck,or around the pipette, or in the cap, or it can be previously adapted tothe bottle, the cap or the pipette.

The invention also relates to a kit of parts comprising a packagecontaining four bottles of the liquid formulation as disclosed hereinand four pipettes intended to remove the needed amount of the liquidformulation and/or instructions.

In another aspect, the invention relates to a kit of parts allowing theextemporaneously preparation of the solutions according to theinvention.

In a preferred aspect, the invention relates to a kit of partscomprising several unit-doses such as ampoules, stick-packs, tubes, etc.These unit-doses are of particular interest for repeated administration.Such unit dosage form comprises 1, ½, ⅓ or ¼ of the daily therapeuticdose of the composition. In another embodiment, the unit dosage formcomprises half the daily therapeutic dose of the composition.

The pharmaceutical compositions of the invention may be used inmammalian subjects, particularly human subjects, for treating anydisease for which this combination is efficient, particularly nervoussystem diseases (e.g., CMT (particularly CMT1A), neuropathic pain, drugor alcohol withdrawal, and Parkinson's disease). They are moreparticularly suitable for treating CMT.

Consequently, in an embodiment, the invention also relates to acomposition of the invention for use for treating CMT.

The invention also relates to a method for treating nervous systemdiseases (e.g. CMT, neuropathic pain, drug or alcohol withdrawal,Parkinson's disease, . . . ), and more particularly to a method fortreating CMT in a subject in need thereof, comprising administering tosaid subject an effective amount of a composition of the invention.

Further aspects and advantages of the invention will be disclosed in thefollowing experimental section, which is illustrative of the invention.

Examples I. Solution as a Dosage Form

The use of both a solution and a solid suspension in a capsuleformulation has been considered. This latter dosage form is based on theuse of a carrier excipient which is solid below 40° C., and in moltenstate at around 55° C. Thus it could be considered as a dosage form ofchoice in order to ensure a homogeneous dispersion of naltrexone (theactive principle present in the lowest quantity in the medication).D-alpha-tocopheryl polyethylene glycol 1000 succinate (VETPGS) has beenchosen as carrier because it is a widely used and well characterizedGRAS excipient.

Stability of the compounds in the solution or suspension was assessed bymeasuring the remaining concentration of the APIs or the apparition ofdegradation products after one week at 25° C. Surprisingly, in thesemi-solid formulation, baclofen concentration dropped of around 14%whereas impurity A (the main degradation product of baclofen) increasedby 75% over one week at 25° C., thereby showing substantial temperature-and time-dependent degradation of baclofen in semi-solid formulation,while the APIs were stable in the solution. The results are summarizedin table 3 below.

TABLE 3 Stability of compounds Compounds Solution Capsule (semi-solid)Baclofen + − Sorbitol + + Naltrexone + + Propyl parabens + N/A +:stability characteristics in accordance with the European Pharmacopeiaspecifications; −: stability characteristics do not meet stabilityrequirement of European Pharmacopeia specifications; N/A: Not Available.

These results have been confirmed by stability assays performed for oneweek at 50° C. which is considered as indicative for long term stabilityof compounds according the pharmacopeial guidance.

II. Preparation and Physicochemical Properties of Solutions of theInvention

Tables 4.A and 4.B below show compositions in the form of solutions thathave been prepared (volume adjusted to 100 mL with the buffer):

TABLE 4.A Composition number 1 2 3 4 5 6 7 8 9 10 11 12 13 Sorbitol 0.210.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21 2.1 (% w/w)Naltrexone 7E−04 7E−04 7E−04 7E−04 7E−04 7E−04 7E−04 7E−04 7E−04 7E−047E−04 7E−04 0.007 (% w/w) Baclofen 0.006 0.006 0.006 0.006 0.006 0.0060.006 0.006 0.006 0.006 0.006 0.006 0.06 (% w/w) Acetate buffer pH 4.5pH 5 pH 5.5 / / / / / / pH 5 / / pH 5.5 0.2M Phosphate / / / pH 4.5 pH 5pH 5.5 / / / / pH 5 / / buffer^(¥) Citrate buffer / / / / / / pH 4.5 pH5 pH 5.5 / / pH 5 / 0.2M Sodium / / / / / / / / / 0.18 0.18 0.18 0.18methyl paraben (% w/v) Sodium / / / / / / / / / 0.02 0.02 0.02 0.02propyl paraben (% w/v) ^(¥)0.01M potassium dihydrogenorthophosphate-0.05M di-sodium hydrogen orthophosphate % w/w: mass in gfor 100 g of the final composition % w/v: mass in g for 100 mL of thefinal composition

TABLE 4.B Composition number 14 15 Sorbitol (% w/w) 4.2 4.2 Naltrexone(% w/w) 0.014 0.014 Baclofen (% w/w) 0.12 0.12 Acetate buffer 0.2M pH5.5 pH 5.0 Sodium methyl paraben 0.18 0.18 (% w/v) Sodium propyl paraben0.02 0.02 (% w/v) Isoamyl acetate (banana flavor) 0.04 0.04 (% w/v) %w/w: mass in g for 100 g of the final composition % w/v: mass in g for100 mL of the final composition

The stability of these compositions under various conditions was tested.As shown below, the solutions of the present invention have been foundstable in a number of tests. For instance, they have remained clear andstable, without precipitation or degradation of the active ingredients(cf. chemical stability results, below). Moreover, the solutions havebeen subjected to alternating refrigeration and room temperatureconditions, without noticing any change in the appearance and stabilityof the solution.

A. Chemical Stability/Microbial Growth

Different formulations have been tested for their stability: changes interms of pH, appearance and coloration were checked over one month at 5°C., 25° C. and 40° C. at one week intervals (data summarized in table5.A). Both citrate and acetate buffered solutions were stable in termsof pH, coloration and appearance (table 5.A), phosphate bufferedsolutions as well. The initial observation of 1 week time point confirmsthat pH, color and appearance of the solutions n° 14 and 15 were stableunder 25° C., 40° C. and a 5-40° C. 24 hour temperature cycling.Solutions n° 14 and 15 were further not prone to changes in baclofen,naltrexone or sorbitol contents under each condition investigated (table5.B). The best stability was observed with a pH 5.5 acetate buffer. Interms of API degradation, citrate and acetate buffered solutions werevery stable, even in the absence of preservative. Phosphate bufferedformulations were found prone to microbial contamination; citratebuffered solutions, though in a less extent, also did in the absence ofa preservative (table 6).

Regarding chemical stability of the APIs, a formulation was consideredstable when the API concentration decreased by less than 5% after 4weeks at 25° C. (table 5.A). Solutions comprising acetate buffer asvehicle (n° 1-3) have shown the best stability. A reduction in baclofencontent was observed in formulations using phosphate buffer as vehicle,especially for the solution n° 5 wherein a fall of 40% (reported to theinitial concentration) in baclofen content is observed. A reduction innaltrexone concentration was observed in the solution n° 5 (phosphatebuffered, pH 5.0). A reduction in sorbitol concentration was alsoobserved in phosphate buffered solutions (n° 4 and 6).

It appears thus that acetate and citrate buffers are the best vehicle interm of stability of the solutions and of chemical stability of theAPIs. It is noteworthy that acetate buffered solutions are not prone tomicrobial contamination (table 6).

TABLE 5.A Solution Number 1 2 3 4 5 6 7 8 9 pH, color, appearance ++++++ +++ + + + ++ ++ ++ (5° C., 25° C., 40° C.) API Baclofen Initial 95.598.1 97.5 93 89.3 98.7 97.5 98.4 97.9 degradation (% nominal) Recovery96.0 98.5 96.4 84.5 52.4 92.7 93.6 96.0 98.4 (4 weeks at NaltrexoneInitial 94.0 95.9 97.1 84.3 82.9 N/A 91.8 91.1 N/A 40° C.) (% nominal)Recovery 93.0 95.5 95.7 86.9 58.4 N/A 91.4 91.7 N/A Sorbitol Initial95.2 99.0 97.1 95.7 95.7 91.9 97.1 98.1 97.1 (% nominal) Recovery 96.799.5 98.6 80.0 94.3 79.5 98.1 96.2 95.7 +++, ++ and +: satisfactionscore (in a decreasing order) N/A: not available

TABLE 5.B Results (mg/mL) baclofen naltrexone sorbitol Solution no 14 1514 15 14 15 Initial 1.18 1.20 0.132 0.134 41.5 41.2 25° C. (1 week) 1.191.18 0.130 0.132 41.2 41.2 40° C. (1 week) 1.19 1.19 0.131 0.133 41.941.6 5-40° C. (1 week 1.20 1.18 0.131 0.131 42.0 41.5 temperaturecycling)

TABLE 6 Microbial contamination Storage temperature Solution number (4weeks) 1 2 3 4 5 6 7 8 9  5° C. no no no +++ +++ +++ ++ ++ ++ 25° C. nono no +++ +++ +++ ++ ++ ++ 40° C. no no no +++ +++ +++ ++ ++ no no: nomicrobial contamination ++ and +++: mid and high microbialcontamination, respectively

Several preservatives have been tested (for example propylene glycol orparabens) to further increase stability, especially for citratecompositions. The use of parabens (sodium methyl paraben and sodiumpropyl paraben, table 7) has been found to lead to citrate basedsolutions resistant to microbial contamination. In contrast, phosphatebuffer based solutions could not be stabilized, nor avoid microbialcontamination, even in the presence of preservatives (tables 6 and 7).

TABLE 7 Solution Number 2 5 8 10 11 12 Vehicle acetate phosphate citrateacetate phosphate citrate Preser- none parabens vative(s) Microbial no+++ ++ no ++ no contam- ination no: no microbial contamination ++ and+++: mid and high microbial contamination, respectively

B. Palatability and Compliance

Palatability is particularly important when talking about oral drugs,and directly linked to the compliance of the patients, especially whentreating chronic diseases. A prerequisite for flavoring agents is to notinterfere with APIs and thereby hamper their stability. Morespecifically, they should not interfere neither with the quality andquantitative analyses of the APIs.

Several flavors have been tested. Some of them were finally discarded asinterfering with the APIs and thereby impeding their furtherquantification. Vanillin and isoamyl acetate were tested for theirpalatability. Briefly, a single drop of each tested formulation wasplaced on the tongue of the volunteers. They were then asked to gradethe palatability of the solutions from 0 (very unpalatable) to 10 (verypalatable).

Isoamyl acetate containing solution obtained the best score.

C. Regulatory Requirements

All medicines have to comply with the pharmacopeial guidance whichlimits for the concentration of impurities in pharmaceutical products.The required criteria are defined by the ICH (International Conferenceon Harmonization of technical requirements for registration ofpharmaceuticals for human use).

Stability of solution n° 13 has been studied; it has been placed at roomtemperature for extended period of time according the specifications ofICH: appearance of the APIs degradation- and related-products has beenassessed over 24 months for solutions stored at 25° C./60% RelativeHumidity (RH).

Impurity A, that is (RS)-4-amino-3-(4-chlorophenyl) butyric acid lactam(Relative Retention Time (RRT, HPLC analysis) 0.82-0.83), is known to begenerated during the synthesis process of baclofen and is known to beincreased during storage of the drug as a degradation product.

Sorbitol related substances that have been searched for are mannitol(RRT 1.21-1.23) and iditol (RRT 0.88-0.89).

As shown in table 8, the product characteristics were compatible withregulatory specifications.

TABLE 8 Results for 24 months ICH Test 25° C./60% RH Sorbitol stabilitySorbitol quantity^(¥) passed Sorbitol related substances^(†) passedBaclofen stability Baclofen quantity^(¥) passed Impurity A^(†) passedNaltrexone stability Naltrexone quantity^(¥) passed Naltrexone relatedsubstances^(†) passed Other Parabens quantity^(¥) passed pH assessment(alarm: change of 0.2 of pH unit passed or more) Microbial quality(alarm: any microbial growth) passed ^(¥)alarm: ±5% (total area) frominitial value; ^(†)alarm: growth by 0.1% (total area) or more; RH:Relative Humidity.

After an initial one week observation, solutions 14 and 15 also passedexisting drug product specification limits. The compositions of table 9represent particularly advantageous embodiments of the invention.

TABLE 9 Formulation Material (% w/v) (% w/w) Sodium methyl paraben 0.1800.176 Sodium propyl paraben 0.020 0.020 D-sorbitol 4.200 4.101Naltrexone HCl 0.014 0.014 Baclofen (RS form) 0.120 0.117 Isoamylacetate (banana) flavor 0.040 0.041 Acetate buffer pH 5.5 to 100 —Sodium acetate trihydrate — 2.221 Glacial acetic acid — 0.241 Water forinjection — 93.070  % w/w: mass in g for 100 g of the final composition% w/v: mass in g for 100 mL of the final composition

D. Product Preparation

Two improved methods were developed for the preparation of thecompositions of the invention. These methods are described below in twodiagrams.

The following diagram provides a first method of manufacture of thecompositions of the invention.

The following second diagram provides another method of the batchmanufacture of the compositions of the invention. This method presentsthe particular advantage of comprising less steps, and further notnecessitates an initial heating step.

Compositions obtained by these methods respond to the pressing need forformulations that combine APIs with high difference in concentrations ina stable form, optionally paraben-free, that can be of particularinterest for children and people constrained to take de medicamentlifelong. Use of glass bottles with graduate pipette or of unit-dosagepacks is of great interest since it improves the compliance inlifelong/chronic invalidating diseases such as Charcot-Marie-Toothdisease.

BIBLIOGRAPHY

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1. A pharmaceutical composition comprising, in the form of a solution:baclofen, sorbitol, and naltrexone as active ingredients, an acetate orcitrate buffer having a pH comprised between 4 and 7, preferably between4.5 and 5.5, and optionally, at least one preservative and/or at leastone flavoring agent.
 2. The composition of claim 1 wherein sorbitol andnaltrexone are present in a relative weight ratio (sorbitol/naltrexone)comprised between 100 and 500, preferably between 200 and
 400. 3. Thecomposition of any one of preceding claims wherein baclofen andnaltrexone are present in a relative weight ratio (baclofen/naltrexone)comprised between 2 and 20, preferably between 5 and
 10. 4. Thecomposition of any one of the preceding claims wherein baclofen,sorbitol and naltrexone are present in the relative weight ratio ofabout 8.6/300/1.
 5. The composition of any one of the preceding claims,wherein the pH of the buffer is about 5.5.
 6. The composition of any oneof the preceding claims, wherein the at least one flavoring agent isisoamyl acetate or vanillin.
 7. The composition of any one of thepreceding claims, wherein the at least one preservative is a paraben. 8.The composition of any one of the preceding claims, wherein the at leastone preservative comprises methyl paraben and/or propyl paraben.
 9. Thecomposition of claim 8, wherein the methyl paraben and/or propyl parabenare used in a concentration of about 0.18% w/v and about 0.02% w/v,respectively.
 10. The composition of any one of preceding claimscomprising: baclofen, sorbitol and naltrexone as active ingredients in arelative weight ratio of about 8.6/300/1, an acetate buffer having a pHof about 5.5, about 0.18% w/v of methyl parahydroxybenzoate and 0.02%w/v propyl parahydroxybenzoate, and about 0.04% w/v of isoamyl acetate.11. The composition of anyone of claims 1-6, which is free of parabenand wherein the buffer is an acetate buffer.
 12. The composition ofanyone of the preceding claims, comprising at least one further compoundselected from antioxidant(s), emulsifier(s), viscosity modifier(s),sweetener(s), flavor enhancer(s), coloring agent(s), co-solvent(s),and/or solubilizer(s).
 13. A composition of anyone of claims 1 to 12 foruse to treat Charcot-Marie-Tooth disease in a subject.
 14. A containercomprising a composition of anyone of the preceding claims.
 15. A kitcomprising a container of claim 14 and instructions.
 16. A method forpreparing a composition of anyone of claims 1 to 12, comprisingproviding baclofen, sorbitol and naltrexone and admixing said activeingredients in solution in a citrate or acetate buffer having a pHcomprised between 4 and 7.